Peptides are an emergent and important class of therapeutics with over forty compounds on the market and nearly 700 more in clinical or pre-clinical trials. During the development of peptide drugs, D-enantiomers of amino acids are frequently incorporated to improve pharmacokinetic and pharmacodynamic properties by lowering susceptibility to proteolysis. Typically, such modifications are introduced in lead compounds by trial-and-error or combinatorial approaches. Our laboratory is developing protCAD (protein Computer Aided Design) to simulate the impact of non-natural amino acids on structure and stability. Using fundamental principles of protein design, we will pursue the computational, structure-based development of peptides with variable chirality, broadly extending our capacity to create safe and potent therapeutics. The success of current computational protein design software is indebted to decades of structural and thermodynamic studies on natural proteins. This leads to an important question - Can simulation tools and molecular parameter sets these programs employ be generalized to the design of a broader class of macromolecules? Preliminary characterization of several computationally designed heterochiral proteins in our lab indicates that tools in protCAD are extendable to non-natural amino acids. In focusing on stereochemically diverse peptides, we will stringently test our fundamental understanding of principles underlying protein structure and stability. Our specific aims focus on three rationally designed, heterochiral lead scaffolds identified using a combination of protCAD and structural bioinformatics tools developed in our laboratory. Each scaffold presents a unique biophysical challenge, exploring contributions of molecular forces and the folding energy landscape in design. These scaffolds address important public health priorities including: (1) developing potent therapeutics for the treatment of diabetes, (2) providing safer molecules for chelation therapy treatment of toxic metal poisoning and (3) providing a novel, rationally designed class of antimicrobials. PUBLIC HEALTH RELEVANCE: We are developing software for the computer-based drug design of peptide therapeutics. Currently, we are focusing our program on three major areas of public health concern. The first is an anti- diabetes peptide hormone that stimulates insulin production and lowers blood sugar. We are also developing peptides that bind toxic metals to promote their safe clearance from the body. Lastly, we are adapting a natural peptide from soil bacteria to produce a new class of antibiotics. Computer engineering of peptide drugs has a lot to contribute both to medicine and to our basic understanding of how proteins function.